Accelerating vasculature imaging in tumor using mesoscopic fluorescence molecular tomography via a hybrid reconstruction strategy.

Mesoscopic fluorescent molecular tomography (MFMT) enables to image fluorescent molecular probes beyond the typical depth limits of microscopic imaging and with enhanced resolution compared to macroscopic imaging. However, MFMT is a scattering-based inverse problem that is an ill-posed inverse problem and hence, requires relative complex iterative solvers coupled with regularization strategies. Inspired by the potential of deep learning in performing image formation tasks from raw measurements, this work proposes a hybrid approach to solve the MFMT inverse problem. This methodology combines a convolutional symmetric network and a conventional iterative algorithm to accelerate the reconstruction procedure. By the proposed deep neural network, the principal components of the sensitivity matrix are extracted and the accompanying noise in measurements is suppressed, which helps to accelerate the reconstruction and improve the accuracy of results. We apply the proposed method to reconstruct in silico and vascular tree models. The results demonstrate that reconstruction accuracy and speed are highly improved due to the reduction of redundant entries of the sensitivity matrix and noise suppression.

Far-Red Aggregation-Induced Emission Hydrogel-Reinforced Tissue Clearing for 3D Vasculature Imaging of Whole Lung and Whole Tumor.

Understanding the vascular formation and distribution in metastatic lung tumors is a significant challenge due to autofluorescence, antibody/dye diffusion in dense tumor, and fluorophore stability when exposed to solvent-based clearing agents. Here, an approach is presented that redefines 3D vasculature imaging within metastatic tumor, peritumoral lung tissue, and normal lung. Specifically, a far-red aggregation-induced emission nanoparticle with surface amino groups (termed as TSCN nanoparticle, TSCNNP) is designed for in situ formation of hydrogel (TSCNNP@Gel) inside vasculatures to provide structural support and enhance the fluorescence in solvent-based tissue clearing method. Using this TSCNNP@Gel-reinforced tissue clearing imaging approach, the critical challenges are successfully overcome and comprehensive visualization of the whole pulmonary vasculature up to 2 µm resolution is enabled, including its detailed examination in metastatic tumors. Importantly, features of tumor-associated vasculature in 3D panoramic views are unveiled, providing the potential to determine tumor stages, predict tumor progression, and facilitate the histopathological diagnosis of various tumor types.

Deep-Brain Three-Photon Imaging Enabled by Aggregation-Induced Emission Luminogens with Near-Infrared-III Excitation.

Understanding the morphology and hemodynamics of cerebral vasculature at large penetration depths and microscale resolution is fundamentally important to decipher brain diseases. Among the various imaging technologies, three-photon (3P) microscopy is of significance by virtue of its deep-penetrating capability and submicron resolution, which especially benefits in vivo vascular imaging. Aggregation-induced emission luminogens (AIEgens) have been recognized to be extraordinarily powerful as 3P probes. However, systematic studies on the structure-performance relationship of 3P AIEgens have been seldom reported. Herein, a series of AIEgens has been designed and synthesized. By intentionally introducing benzene rings onto electron donors (D) and acceptors (A), the molecular distortion, conjugation strength, and the D-A relationship can be facilely manipulated. Upon encapsulation with DSPE-PEG2000, the optimized AIEgens are successfully applied for 3P microscopy with emission in the far-red/near-infrared-I (NIR-I, 700-950 nm) region under the near-infrared-III (NIR-III, 1600-1870 nm) excitation. Impressively, using mice with an opened skull, vasculature within 1700 µm and a microvessel with a diameter of 2.2 µm in deep mouse brain were clearly visualized. In addition, the hemodynamics of blood vessels were well-characterized. Thus, this work not only proposes a molecular design strategy of 3P AIEgens but also promotes the performance of 3P imaging in cerebral vasculature.

Noninvasive Visualization of Sub-5 mm Orthotopic Hepatic Tumors by a Nanoprobe-Mediated Positive and Reverse Contrast-Balanced Imaging Strategy.

Delineation of small malignant lesions and their vasculature enables early and accurate diagnosis of hepatocellular carcinoma (HCC). However, it remains challenging to identify these features simultaneously by noninvasive imaging technology. Reverse contrast imaging emerges as a powerful means to detect early-stage HCC by taking inspiration from the intrinsic liver phagocytosis toward exogenous agents to generate negative tumor-to-normal tissue signals. However, this mechanism conflicts with the signal-enhancing requirements for vasculature visualization. Here, we solve this conundrum by designing a positive and reverse contrast-balanced imaging strategy based on a multifunctional PEG-Ta2O5@CuS nanoprobe that combines advanced gemstone spectral computer tomography (GSCT) with photoacoustic (PA) imaging. The nanoprobe exhibits preferential accumulation in Kupffer cells and hepatocytes over tumor cells, and its spectral properties are well matched with GSCT, leading to the enhancement of reverse contrast signals that enable clear delineation of 2-4 mm orthotopic HCC lesions. Meanwhile, its strong PA imaging capability at the second near-infrared (NIR-II) window makes vascular evaluation accessible by monitoring the positive signal enhancement derived from the limited tumor accumulation of the nanoprobe. In addition, the nanoprobe enables NIR-II photohyperthermia for timely tumor ablation. Overall, this proposed strategy shows potential in early detection and theranostics of HCC for improved clinical outcomes.

Amphiphilic DTPA Multimer Assembled on Icosahedral Closo-Borane Motif as High-Performance MRI Blood Pool Contrast Agent.

A multimeric MRI blood pool contrast agent based on the closo-borane motif is reported. Twelve copies of an amphiphilic DTPA chelate with amine end groups are appended on carbonate-functionalized closo-borane motif using carbamate linkages. The presence of peripheral phenyl groups on the modified DTPA chelates results in high human serum albumin binding, high relaxivity, and excellent contrast enhancement in vitro and in vivo.

High resolution, label-free photoacoustic imaging of live chicken embryo developing in bioengineered eggshell.

Chicken embryos have been proven to be an attractive vertebrate model for biomedical research. They have helped in making significant contributions for advancements in various fields like developmental biology, cancer research and cardiovascular studies. However, a non-invasive, label-free method of imaging live chicken embryo at high resolution still needs to be developed and optimized. In this work, we have shown the potential of photoacoustic tomography (PAT) for imaging live chicken embryos cultured in bioengineered eggshells. Laser pulses at wavelengths of 532 and 740 nm were used for attaining cross-sectional images of chicken embryos at different developmental stages. Cross-sections along different depths were imaged to gain knowledge of the relative depth of different vessels and organs. Due to high optical absorption of vasculature and embryonic eye, images with good optical contrast could be acquired using this method. We have thus reported a label-free method of performing cross-sectional imaging of chicken embryos at high resolution demonstrating the capacity of PAT as a promising tool for avian embryo imaging.

Enhanced contrast acoustic-resolution photoacoustic microscopy using double-stage delay-multiply-and-sum beamformer for vasculature imaging.

In acoustic-resolution photoacoustic microscopy (AR-PAM) systems, the lateral resolution in the focal zone of the ultrasound (US) transducer is determined by the numerical aperture (NA) of the transducer. To have a high lateral resolution, a large NA is used. However, the larger the NA, the smaller the depth of focus [DOF]. As a result, the lateral resolution is deteriorated at depths out of the focal region. The synthetic aperture focusing technique (SAFT) along with a beamformer can be used to improve the resolution outside the focal region. In this work, for image formation in AR-PAM, we propose the double-stage delay-multiply-and-sum (DS_DMAS) algorithm to be combined with SAFT. The proposed method is evaluated experimentally using hair targets and in vivo vasculature imaging. It is shown that DS_DMAS provides a higher resolution and contrast compared to other methods. For the B-mode images obtained using the hair phantom, the proposed method reduces the average noise level for all the depths by about 134%, 57% and 23%, compared to the original low- resolution, SAFT+DAS and SAFT+DMAS methods, respectively. All the results indicate that the proposed method can be an appropriate algorithm for image formation in AR-PAM systems.